Cervical cancer is the second most common cancer among women throughout the world (Ferlay J, Shin H R, Bray F, Forman D, Mathers C, Parkin D M. Int J Cancer. 2010. 127: 2893-2917.), the 5-year survival rate of the cervical cancer is about 80% or more by the national cancer registration program, and thus, it is known that the cancer is detected early and the survival rate is increased. It is found that Human Papillomavirus (HPV) is present in 99.7% of cervical cancer patients, and it is known that the survival of the HPB infection causes transition to invasive cervical cancer and cervical precancers.
Currently, it is known that gene types of HPV are 100 or more types and gene types causing diseases to the human among them are about 30 types. The gene types causing diseases to the human are classified into high-risk groups 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82, low-risk groups 6, 11, 40, 42, 43, 44, 54, 61, 70, 72, and 81, and potential-risk groups 34, 57, and 83. HPV having each gene type is discovered specifically according to location of lesions and progression of the lesion and thus, the biological diversity of HPV infection has been recognized.
The most common method for diagnosing infection of the HPV is a cervical papanicolaou smear (hereinafter, a Pap smearing test) that performs a cell diagnostic test by using the eliminated cells obtained from the cervix, and it was known that the test method has high availability as a cervical cancer selection test due to economic reasons in which a testing method is simple and cost is low, but there is a disadvantage in that the sensitivity is approximately 20˜50% and the false negative rate is very high (Hwang T S, Jeong J K, Park M, Han H S, Choi H K, Park T S. Gynecol Oncol. 2003. 90: 51-56). Particularly, low sensitivity and predictive value for high-grade squamous intraepithelial lesion (hereinafter, referred to as HSIL) are reported, and as compared with squamous cell carcinoma, due to low selection for grandular lesion or adenocarcinoma, it is difficult to initial-diagnose the cervical cancer, and thus, there are many limitations in the Pap smearing test in the cervical cancer diagnosis (Kim Y S, Lee H J, Lee G G. Korean J. Clin. Pathol. 2001. 21: 210-214; Kwon H S, Kim Y T, Kim J W, Kim S H. Korean J Gynecol Oncol Colposc. 2002. 13: 327-335.).
Further, a test method using a colposcope may obtain an accurate result compared with the Pap smear test, but requires skilled technicians and expensive equipment, and there is a disadvantage in that the infection of HPV cannot be distinguished.
In the process to progress to the cervical cancer, as the HPV is known as an important factor, it is important to find a presence of HPV DNA in the initial diagnosis of the cervical cancer in addition to the Pap test as a cytological test method which has been used in the existing cervical cancer test.
As it is known that the progressing to the cervical cancer was associated with the infection of human papillomavirus (hereinafter, referred to as HPV), many HPV DNA test methods including an HPV gene type testing method of testing HPV gene types based on an L1 gene coding a capsid protein from a method of detecting a HPV DNA from the cervix have been developed and commercialized. Currently, the molecular diagnostic methods have been used together as an assisting test of the Pap smear test (Thomas I, Liesje G, Ryan S. J Clin Microbiol. 1999. 37: 2508-2517). The use is also increased in Korea (Cho E J, Do J H, Kim Y S, Bae S, Ahn W S. J Med Microbiol. 2011. 60: 162-171).
As the HPV DNA test method, representatively, a method of finding a presence of DNA of HPV by using polymerase chain reaction (PCR) or a method of testing gene types of HPV by using a DNA chip or a reverse blot hybridization assay (REBA) is known.
In the HPV DNA test and the HPV Genotyping test, it is advantageous that the sensitivity is very high and the infected HPV gene type can be known, but there is a limit that the analytical sensitivity is too high and thus even in low-grade lesion and normal opinions as well as the high-grade lesions SCC and HSIL, it is detected at a high ratio of approximately 40 to 50%. The HVP infection can be detected by only the presence of the HPV DNA, but there is a disadvantage in that the cervical cancer may not be immediately diagnosed.
When the cervix is infected with the HPV, the HPV oncogenes E6/E7 are overexpressed and a function of a cancer suppressor protein such as p53 and pRB is inhibited to cause the cancer.
However, according to recent studies for some years, even in the inflammation step before generating the cancer or a normal cervix as well as a cervical cancer patient, the HPV DNA positive rate is too high, and thus, even though the HPV DNA is detected, it is difficult to treat and prevent the clinical cervical cancer.
Meantime, in order to detect the HPV DNA and the gene types, a site encoding a L1 (late gene 1) capsid protein having the largest size in the nucleic acid of the HPV has been developed as a target, but detecting the gene expression level by targeting mRNA encoding E6/E7 as the protein expressed when inducing the cancer is more available than determining cervical cancer or a prognosis of the cervical cancer.
Until now, the development of the HPV mRNA test method which targets the HPV oncogenes E6, E7 mRNA is slight in Korea, and in the domestic medium and large hospitals, the HPV DNA gene type tests have been increased. However, the HPV DNA positive rate is high in the cervical cancer and in normal, and thus, it is difficult to be immediately applied to direct clinical treatment or prevention treatment.
Recently, a test method of targeting mRNA encoding E6 and E7 genes as the oncogenes in an HPV high-risk group other than the test using the DNA of the HPV has been developed and a real-time NASBA test method that may detect the E6, E7 mRNA of HPV 16, 18, 31, 33, 45 gene types which are most present in the cervical cancer was already commercialized worldwide. However, the test kits are too expensive (price: 30,000 won/test), and for the real-time NASBA, a dedicated analysis machine is required. However, in the current medium and large hospitals, the dedicated analysis machine is not possessed and thus, substantially, it is difficult to be applied to the clinical test. Further, in the case of the current commercialized E6, E7 mRNA test method, since 5 HPV gene types HPV 16, 18, 31, 33, and 45 which are pandemic worldwide are included, the HPV gene types had a difference from the HPV gene types separated from the cervical cancer caused in Korea, and thus, there is a limit to apply the method to domestic patients.